Protective Effect of N-Acetyl Cysteine in Carbon Tetrachloride

1735-2657/05/42-118-123
IRANIAN JOURNAL OF PHARMACOLOGY & THERAPEUTICS
Copyright © 2005 by Razi Institute for Drug Research (RIDR)
IJPT 4:118-123, 2005
Protective Effect of N-Acetyl Cysteine in Carbon
Tetrachloride-Induced Hepatotoxicity in Rats
NARASIMHANAIDU KAMALAKKANNAN, RAJAGOPALAN RUKKUMANI, KODE ARUNA,
PENUMATHSA SURESH VARMA, PERIYASAMY VISWANATHAN and VENUGOPAL PADMANABHAN
MENON
Department of Biochemistry (N.K, R.R, K.A., P.S.V., V.P.M.); Department of Pathology (P.V.); Rajah Muthiah Medical
College and Hospital, Annamalai University, Annamalainagar, Tamil Nadu, India.
Received August 12, 2005; Revised October 29, 2005; Accepted November 5, 2005
This paper is available online at http://ijpt.iums.ac.ir
ABSTRACT
The present study determines the efficacy of N-acetyl cysteine (NAC) on marker enzymes, lipid peroxidation and antioxidants in carbon tetrachloride induced hepatotoxicity in rats. Carbon tetrachloride (CCl4) (3
mL/kg/week) administered subcutaneously to albino Wistar rats for a period of three months significantly
increased the activities of marker enzymes in plasma such as aspartate transaminase, γ-glutamyl transferase and alkaline phosphatase and increased the levels of thiobarbituric acid reactive substances and
hydroperoxides in plasma and tissues (liver and kidney). A significant decrease in the levels of plasma
antioxidants (glutathione, vitamin C and vitamin E) was also noted. Further, a decrease in the concentration of glutathione and the activities of superoxide dismutase, catalase and glutathione peroxidase in the
tissues were observed. N-acetyl cysteine (150 mg/kg) was orally administered to normal and carbon tetrachloride-treated rats for a period of three months. N-acetyl cysteine decreased the activities of marker
enzymes, lipid peroxidation and improved the antioxidant status in carbon tetrachloride-treated rats. But
there were no significant alterations in these parameters in normal rats treated with N-acetyl cysteine.
Histopathological observations of the liver also showed the protective effect of N-acetyl cysteine in carbon
tetrachloride-induced hepatotoxicity in rats. The results of this study show the protective action of N-acetyl
cysteine in carbon tetrachloride-induced hepatotoxicity in rats. This is mainly due to the effective antioxidant potential of N-acetyl cysteine.
Keywords: N-acetyl cysteine, Hepatotoxicity, Carbon tetrachloride
Carbon tetrachloride is commonly used as a model
to evaluate hepatotoxicity [1]. Carbon tetrachloride metabolism begins with the formation of the trichloromethyl free radical, CCl3˙ through the action of the
mixed function cytochrome P450 oxygenase system of
the endoplasmic reticulum [2]. The CCl3 radical reacts
with various biologically important substances such as
amino acids, nucleotides and fatty acids, as well as proteins, nucleic acids and lipids. In the presence of oxygen, the CCl3 radical is converted to the trichloromethyl
peroxy radical (CCl3OO˙). This radical is more reactive
and is capable of abstracting hydrogen from polyunsaturated fatty acids (PUFA) to initiate the process of lipid
peroxidation [3].
Modulation of cellular thiols has been used to protect the hepatocytes against attack by reactive oxygen
intermediates and is currently being investigated as a
novel therapeutic strategy in different liver pathologies.
118-123 | IJPT | July 2005 | vol. 4 | no. 2
One of the most extensively studied agents is N-acetylL-cysteine, a sulfur-containing amino acid that possesses many biological properties. It is credited as a
drug with multiple therapeutic applications [4]. NAC
could significantly interfere with the pathophysiology of
free radicals producing drug induced oxidative stress
[5].
Reports have shown that NAC treatment protects
against acetaminophen hepatotoxicity in patients [6] and
in rats [7, 8]. Also, there are few reports on the protective role of NAC in CCl4-induced toxicity in patients [911] and in rats [12-15]. But there are no detailed reports
on the antioxidant defense of NAC in CCl4-induced
hepatotoxicity in a long run. Hence we considered it
worthwhile and carried out this investigation to assess
the effect of NAC on marker enzymes, nonenzymic and
enzymic antioxidants in CCl4-induced hepatotoxicity in
rats.
ijpt.iums.ac.ir | 119
N-Acetyl Cysteine in Carbon Tetrachloride-Induced Hepatotoxicity
Table 1. Effect of NAC on the activities of marker enzymes in plasma
of normal and CCl4-treated rats.
Groups
ALP (IU/L)
GGT (IU/L)
AST (IU/L)
Normal
Normal + NAC
CCl4
CCl4 + NAC
72.61±5.13a
70.18 ±7.49a
193.1±16.28b
89.04±5.44c
0.57±0.04 a
0.54±0.06a
1.65±0.11b
0.70±0.04c
73.12±6.47a
71.24±5.33a
139.0±9.42b
83.39±5.49a
Each value is mean ± S.D. for 6 rats in each group.
Values not sharing a common superscript (a,b,c) differ significantly at
p < 0.05.
MATERIALS AND METHODS
Animals
Male albino Wistar rats of body weight 150-180 g
were obtained from the Central Animal House, Rajah
Muthiah Medical College and Hospital, Annamalai
University and were maintained there. The rats were
housed in polypropylene cages lined with husk. They
were fed on a standard pellet diet (Agro Corporation
Private Ltd., Bangalore, India) and water ad libitum.
Materials
N-acetyl-L-cysteine was obtained from Sigma
Chemical Company, St. Louis, MO, USA. CCl4 was
purchased from Merck Ltd., Mumbai, India. All other
chemicals and biochemicals used in our study were of
high analytical grade.
Experimental Design
In our study, a total of 24 rats were used. The rats
were divided into 4 groups of 6 rats each.
• Group I. Normal control rats.
• Group II. Normal rats orally administered with
NAC (150 mg/kg body weight) [16].
• Group III. Rats subcutaneously injected with
CCl4 (3 mL/kg body weight/week) [17].
• Group IV. Rats orally administered with NAC
(150 mg/kg body weight) along with subcutaneous injection of CCl4 (3 mL/kg body
weight/week).
The experiment was carried out for a period of three
months. All the experimental protocols were approved
by the Ethical Committee of Annamalai University.
After the last treatment, the animals were fasted overnight and killed by cervical dislocation. Blood was collected in heparinised tubes. Plasma was separated and
used for various biochemical estimations. Liver and
kidney were collected in ice-cold containers, washed
with saline, homogenised with appropriate buffer and
used for various estimations.
In plasma, the levels of marker enzymes such as
AST [18], ALP [19], GGT [20] and the levels of
TBARS [21], hydroperoxides [22], GSH [23], vitamin C
[24] and vitamin E [25] were estimated by standard procedures.
In liver and kidney, the concentration of TBARS
[21], HP [22], GSH [23], superoxide dismutase [26],
catalase [27] and glutathione peroxidase [28] were also
estimated.
For histopathological studies, livers from animals of
different groups were perfused with 10% neutral formalin solution. Paraffin sections were made and stained
using hematoxylin-eosin (H&E) stain. After staining,
the sections were observed under light microscope and
photographs were taken.
Statistical Analysis
Statistical analysis was performed using one way
analysis of variance (ANOVA) followed by Duncan’s
Multiple Range Test (DMRT). The values are mean ±
S.D. for 6 rats in each group. p-Values < 0.05 were considered as significant.
RESULTS
Effect of NAC on Marker Enzymes
The effect of oral administration of NAC on plasma
AST (aspartate transaminase), GGT (γ-glutamyl transferase) and ALP (alkaline phosphatase) activities in
normal and CCl4-induced rats is presented in Table 1. A
significant increase in the activities of these marker enzymes were observed in CCl4-treated rats. On treatment
with NAC, the activities of these enzymes were found to
be significantly decreased.
Effect of NAC on Lipid Peroxidative Products and
Nonenzymic Antioxidants in Plasma
Table 2 shows the changes in the levels of plasma
TBARS (thiobarbituric acid reactive substances), HP
(hydroperoxides), vitamin C, vitamin E and GSH (glutathione) in normal and CCl4-treated rats. There was a
significant increase in the levels of TBARS and hydroperoxides and a decrease in vitamin C, vitamin E and
GSH in CCl4-treated rats. Treatment with NAC significantly decreased the elevated levels of TBARS and hydroperoxides and increased the levels of vitamin C, vitamin E and GSH in plasma.
Effect of NAC on Lipid Peroxidative Products in the
Tissues
There was a significant increase in the concentration
of TBARS and hydroperoxides in the tissues (liver and
kidney) of CCl4-administered rats (Table 3). Oral administration of NAC significantly decreased the concen-
Table 2. Effect of NAC on the levels of TBARS and hydroperoxides and nonenzymic antioxidants in plasma of normal and CCl4-treated rats.
Hydroperoxides
TBARS
Vitamin C
Vitamin E
Groups
GSH (mg/dL)
(nM/mL)
(mg/dL)
(mg/dL)
(values × 10-5 mM/dL)
Normal
0.14 ± 0.01a
7.13 ± 0.52a
23.25 ± 1.89a
1.70 ± 0.88a
1.33 ± 0.09a
Normal + NAC
6.34 ± 0.33a
24.30 ± 1.64a
1.88 ± 0.92a
1.46 ± 0.09a
0.11 ± 0.01a
CCl4
28.64 ± 1.84b
10.71 ± 1.29b
0.81 ± 0.10b
0.67 ± 0.04b
0.52 ± 0.06b
CCl4 + NAC
13.58 ± 1.30c
20.43 ± 2.17a
1.52 ± 0.74c
1.14 ± 0.08c
0.27 ± 0.04c
Each value is mean ± S.D. for 6 rats in each group.
Values not sharing a common superscript (a,b,c) differ significantly at p < 0.05.
120 | IJPT | July 2005 | vol. 4 | no. 2
Kamalakkannan et al.
Table 3. Effect of NAC on TBARS and hydroperoxides in the tissues of normal and CCl4-treated rats.
Hydroperoxides (mM 100/g wet tissue)
TBARS (mM 100/g tissue)
Groups
Liver
Kidney
Liver
Kidney
Normal
Normal + NAC
CCl4
CCl4 + NAC
0.66±0.04a
0.61±0.04a
3.80±0.24b
1.22±0.07c
1.13±0.08a
1.37±0.08a
5.27±0.44b
2.83±0.20c
83.81±7.09a
88.83±6.27a
249.07±22.61b
112.67±8.07c
69.08±6.31a
65.50±6.07a
209.51±18.18b
97.68±7.44c
Each value is mean ± S.D. for 6 rats in each group.
Values not sharing a common superscript (a,b,c) differ significantly at p < 0.05.
tration of TBARS and hydroperoxides in all the tissues.
Effect of NAC on Tissue Enzymic Antioxidants
Table 4 presents the activities of antioxidant enzymes (superoxide dismutase [SOD] and catalase) in
normal and CCl4-treated rats. The activities of these
enzymes were significantly decreased in the tissues of
CCl4-administered rats. On treatment with NAC, the
decreased activities of these enzymes were brought back
to near normal.
Table 5 shows the concentration of GSH and the activity of glutathione peroxidase in the tissues of CCl4administered rats. The concentration of GSH and the
glutathione peroxidase (GPx) activity were found to be
decreased upon CCl4 administration. Oral administration of NAC restored the changes brought about by the
administration of CCl4.
Histological Examination of the Liver
Histopathological examination of the liver sections
from normal rats showed normal parenchymal architecture (Fig 1-A). The liver of rats treated with NAC alone
did not show any noticeable alterations (Fig 1-B). In rats
treated with CCl4 alone, the liver sections showed thickening of blood vessels (Fig 1-C) and microvesicular
fatty changes around portal triad (Fig 1-D). In rats
treated with CCl4 + NAC, only mild sinusoidal dilatation was observed (Fig 1-E).
Oral administration of NAC to normal rats did not
show significant effect in any of the parameters studied.
DISCUSSION
Carbon tetrachloride induced lipid peroxidation results in changes of structures of the endoplasmic reticulum and other membranes, loss of metabolic enzyme
activation and reduction of protein synthesis leading to
liver damage [29]. In this study, CCl4 administration to
rats lead to a marked elevation in the levels of plasma
AST, GGT and ALP. This might be due to the release of
these enzymes from the cytoplasm, into the blood circulation rapidly after rupture of the plasma membrane and
cellular damage [30]. Treatment with NAC significantly
reduced the levels of these marker enzymes in CCl4
treated rats. This implies that NAC tends to prevent
liver damage, suppresses the leakage of enzymes
through cellular membranes, preserves the integrity of
the plasma membranes and hence restores these enzymes levels.
Lipid peroxidation as well as altered levels of some
endogenous scavengers are taken as indirect in vivo reliable indices for oxidative stress [31]. Increased levels of
TBARS and hydroperoxides were observed in plasma
and tissues of CCl4-treated rats. Lowered levels of
TBARS and hydroperoxides by oral administration of
NAC could be related to its antioxidant capacity to
scavenge reactive oxygen species. NAC contains free
sulfhydryl groups and it may directly react with electrophilic compounds such as free radicals [32].
Excessive liver damage and oxidative stress caused
by CCl4 depleted the levels of GSH, vitamin C and vitamin E in our study. Oxidative stress induced by CCl4
results in the increased utilisation of GSH and subsequently the levels of GSH is decreased in plasma and
tissues. Utilisation of vitamin E is increased when oxidative stress is induced by CCl4 and this shows the protective role of vitamin E in mitigating the elevated oxidative stress. Vitamin C scavenges and destroys free
radicals in combination with vitamin E and glutathione
[33]. It also functions cooperatively with vitamin E by
regenerating tocopherol from the tocopheroxyl radical
[34]. A decrease in the levels of vitamin C may indicate
increased oxidative stress and free radical formation in
CCl4-induced liver injury.
N-acetyl cysteine treatment effectively restored the
depleted levels of these nonenzymic antioxidants. NAC
could significantly interfere with the pathophysiology of
free radical producing drug induced oxidative stress [5].
Wong et al. have reported the ability of NAC in regulating GSH concentration and thus protect liver damage
from reactive metabolites formed from CCl4 [15]. Increase in GSH levels could also contribute to the recycling of other antioxidants such as vitamin E and vitamin C [35].
A major defense mechanism involves the antioxidant enzymes including SOD, catalase and GPx which
Table 4. Effect of NAC on the activities of superoxide dismutase and catalase in the tissues of normal and CCl4-treated rats.
Catalase (µmole of H2O2 consumed/min/mg protein)
SOD (Units/mg protein)
Groups
Liver
Kidney
Liver
Kidney
Normal
Normal + NAC
CCl4
CCl4 + NAC
15.64±1.29a
16.94±1.31a
6.17±5.32b
13.90±1.04c
16.11±1.07a
16.81±1.39a
9.06±0.85b
15.22±1.41c
61.31±4.23a
57.62±5.04a
44.36±4.97b
57.61±4.17a
SOD units: Enzyme concentration required to inhibit the O.D at 560nm of chromogen production by 50% in 1 min.
Each value is mean ± S.D. for 6 rats in each group.
Values not sharing a common superscript (a,b,c) differ significantly at p < 0.05.
64.64±5.25a
63.20±5.99a
38.06±4.06b
59.81±5.24c
N-Acetyl Cysteine in Carbon Tetrachloride-Induced Hepatotoxicity
ijpt.iums.ac.ir | 121
Fig 1. (A) Liver section of normal rat showing normal parenchymal
architecture (H&E 10×). (B) Treatment with NAC to normal rats
showed no histological alterations (H&E 10×). (C) Thickening of
blood vessels caused by CCl4 administration (H&E 10×). (D) Microvesicular fatty changes around portal triad in rats treated with CCl4
(H&E 10×). (E) CCl4 + NAC administration showing mild sinusoidal
dilatation (H&E 10×).
convert active oxygen molecules into non-toxic compounds.CCl4-administration decreased the activities of
these antioxidant enzymes and GSH concentration in
the tissues. Oral administration of NAC restored the
activities of these enzymes and glutathione in rats
treated with CCl4. NAC contributes significantly to the
intracellular antioxidant defense system by acting as a
powerful consumer of superoxide, singlet oxygen and
hydroxyl radicals [36].
NAC induces its beneficial effect mainly through
maintaining –SH groups of enzymes and membrane
proteins in the reduced state [37]. NAC can prevent the
hepatic GSH depletion as well it can slow the decrease
of hepatic GSH. The hepatoprotective effects of NAC
may also be due to its ability to enhance glutathione
production by providing more substrate for reactive
intermediates that promote detoxification mechanisms
[38]. This also may be the reason for the restoration of
other antioxidant enzymes such as SOD and catalase.
Histopathological examination of the liver also provided supporting evidence for our study. Rats treated
with NAC reduced the damage caused by CCl4 administration. This clearly indicates the membrane stabilizing
effect of NAC by scavenging free radicals and preserving the integrity of the membranes.
The overall results of our study confirm the protective
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Kamalakkannan et al.
Table 5. Effect of NAC on the concentration of glutathione and glutathione peroxidase in the tissues of normal and CCl4-treated rats.
Glutathione peroxidase
GSH (mM 100/g tissue)
Groups
(µg of GSH consumed/min/mg protein)
Liver
Kidney
Liver
Kidney
Normal
Normal + NAC
CCl4
CCl4 + NAC
160.30±12.23a
168.18±14.60a
80.98±9.04b
142.37±11.67c
132.85±12.46a
139.67±11.49a
68.46±7.11b
127.48±10.28c
10.65±0.85a
11.12±0.94a
3.84±0.30b
8.90±0.81c
8.93±0.71a
9.10±0.87a
4.11±0.44b
7.78±0.62c
Each value is mean ± S.D. for 6 rats in each group.
Values not sharing a common superscript (a,b,c) differ significantly at p < 0.05.
linearis) on CCl4-induced liver damage in rats. Physiol Res
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effect of N-acetyl cysteine in CCl4-induced hepatotoxicity in rats by its ability to stabilize cell membranes,
scavenge free radicals and antioxidant properties. The
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of NAC as an effective hepatoprotectant.
15. Wong CK, Ooi VEC, Wong CK. Protective effects of N-acetyl
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17. Akila GV, Rajakrishnan V, Viswanathan P, Rajashekaran KN,
Menon VP. Effects of curcumin on lipid profile and lipid peroxidation status in experimental hepatic fibrosis. Hepatol Res
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